Modified Project Summary/Abstract Section This project is the R00 phase of a K99/R00 award to be completed in the Department of Pharmacology and Physiology at George Washington University. In this project, I will investigate the role of inhibitory synapses on VTA dopamine neurons in animal models of resilience and susceptibility to stress-induced anhedonia. Dopamine neurons of the ventral tegmental area (VTA) are a crucial part of the brain's reward processing system, and function of these neurons is greatly influenced by stress. In particular, activity of dopamine neurons projecting to the nucleus accumbens has been causally linked to an animal's behavioral response to stress. Inhibitory synapses onto dopamine neurons powerfully modulate their activity, and are thus poised to be a significant mediator of stress's effects on the VTA. In this proposal, I will take a multidisciplinary approach, utilizing electrophysiological, optogenetic, chemogenetic, and behavioral techniques to address the hypothesis that inhibitory synapses onto nucleus accumbens-projecting VTA dopamine neurons are a key determinant of an individual's behavioral responses to stress. I propose two aims, revised from my original K99/R00 application. In the first, I will examine inhibitory synaptic physiology and plasticity onto nucleus accumbens projecting dopamine neurons in mice exhibiting differential responses to two forms of repeated stress: chronic social defeat and subchronic variable stress. In the second, I will examine changes in the strength of two specific inputs (local VTA interneurons and RMTg projections) onto nucleus accumbens-projecting dopamine neurons following chronic social defeat and the ability of chemogenetic manipulation of these inputs to promote resilience to this stressor. These studies hold the potential to contribute significantly to our understanding of how the reward system is altered by stress and may lead to novel avenues for the development of therapeutic treatments for depression and other stress-linked disorders.